The enteric nervous system (ENS) is a part of the peripheral nervous system (PNS) that operates largely independently of the central nervous system (CNS) to coordinate the complex behaviors of the gastrointestinal (GI) tract. ENS abnormality or dysfunction can lead to dysmotility syndromes include achalasia, gastro-esophageal reflux disease, delayed emptying of the stomach, abdominal pain and bloating, diarrhea and constipation[1]. Besides congenital motility disorders of ENS [eg Hirschsprung disease (HSCR)[2]], neuron degeneration also occurs in a large number of other diseases or pathophysiological conditions, such as diabetic gastroparesis, intestinal pseudo-obstruction of motility, and age-related neuronal loss in ENS[3]. Remarkably, recent reports have shown that lesions in ENS occur at very early stages of these diseases, even before the involvement of the central nerve system [4]. So far, however, no effective therapy is available for these syndromes or disorders, and thus new and effective treatments are urgently needed[1,3,5].
Advances in stem cell research over the past two decades have opened up the possibility of using stem cells to treat neuron injury or degeneration diseases [6,7,8]. Multiple types of stem cells, including embryonic stem cells (ESC)[9], ESC-derived neural precursors[10], induced pluripotent stem cells (iPSC)[11], neural stem cells[12], neural crest-derived stem cell[13] and enteric nervous system stem cells[14,15], have been demonstrated to be capable of being converted to neural and glial lineage [6,7,16,17].
Adult bone marrow-derived mesenchymal stem cells (BMSCs) are multipotent progenitors that are capable of osteogenic, adipogenic and chondrogenic differentiation, as well as displaying transdifferentiation potential beyond the mesenchymal lineages, including differentiation into neurons (although this remains controversial) [18,19,20,21,22,23]. In addition, due to their active expansion capacity, high plasticity, and especially their low immunogenicity, BMSCs remain as unique and attractive candidates for allogenic cell-replacement therapies [23, 24A and 24B]. By December 2013, there had been 347 registered clinical trials using mesenchymal stem/stromal cells, according to “Clinicaltrials.gov registry on Dec. 15, 2013” [See also 24B, especially FIG. 1].
Functional improvement through BMSC therapy has been reported in animal models of CNS injury, such as traumatic brain injury or spinal cord injury et al [8,25,26,27,28,29]. While some of the underlying mechanisms have been well documented, others are controversial or being challenged or poorly understood, including involvements of direct-transdifferentiation of BMSCs into neurons, spontaneous cell fusion, anti-inflammatory property and modulation of neurotrophic mediator[18,19,30,31,32]. In addition, it is unclear how BMSCs take part in ENS circuit repair[33].
The properties and clinical applications of BMSC have always been a focus of debate since data from different reports are not always consistent, most likely due to the lack of disease-specific standardization or less-than-optimal experimental conditions [18,19,20,21]. For these reasons, MSC researchers have made significant efforts, by modulating microenvironments of MSCs (“reconditioning” or “reprograming” of MSC) before and after transplantation, on improving therapeutic potential and consistency[37,38,39]. Nevertheless, there remains a desire in the art to develop BMSC populations, which may used to treat ENS-related disorders.